PhIP-induced skin tumors were subjected to mutation screening, which identified genetic changes in Hras (7/40, 17.5%) and Tp53 (2/40, 5%), but not in Ctnnb1, a commonly mutated gene in PhIP-induced colon tumors.
We also observed the inactivation of β-catenin/TCF signaling after CBB1003 treatment, consistent with the positive correlations among LSD1, LGR5, β-catenin and c-Myc expression in human colon tumor and adenoma tissues.
The mechanism by which sulindac sulfide and the cGMP/PKG pathway inhibits colon tumor cell growth involves the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin T-cell factor transcriptional activity, leading to downregulation of cyclin D1 and survivin.
In mice, SMAC deficiency significantly increased the incidence and size of colon tumors induced by azoxymethane (AOM)/dextran sulfate sodium salt (DSS), and highly enriched β-catenin hot spot mutations.
SPDEF inhibited the expression of β-catenin-target genes in mouse colon tumors, and interacted with β-catenin to block its transcriptional activity in CRC cell lines, resulting in lower levels of cyclin D1 and c-MYC.
A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity.
Activation of the β-catenin/T-cell factor (TCF) complex occurs in most colon tumors, and its actions correlate with the neoplastic phenotype of intestinal epithelial cells.
In a converse experiment, the forced expression of LPP3 in human colon tumor (SW480) cells potentiated tumor growth via increased β-catenin stability and CYCLIN-D1 synthesis.
Murine deletion of Cck2r abrogated progastrin-dependent increases in colonic proliferation, mucosal thickness, and beta-catenin and CD44 expression in the colon tumor.
In the colon tumors, beta-catenin mutations were detected at a higher frequency after caffeine posttreatment, and there was a shift toward more tumors harboring substitutions of Gly34 with correspondingly high protein and messenger RNA expression seen for both beta-catenin and c-Myc. c-Myc expression exhibited concordance with tumor promotion, and there was a concomitant increase in cell proliferation versus apoptosis in colonic crypts.
The finding of LOH in ACF with normal expressions of adenomatous polyposis coli (APC) and beta-catenin proteins suggests that LOH can occur very early in colon neoplasia and perhaps even before APC mutations.
In addition, we found that the beta-catenin protein was accumulated in cytoplasm and nuclei of MDF and the frequent beta-catenin gene mutations in the colon tumors.